24 May 2013 EMA/339116/2013 Assessment report cyproterone acetate/ethinylestradiol (2 mg/0.035 mg) containing medicinal products Procedure under Article 107i of Directive 2001/83/EC Procedure number: EMEA/H/A-107i/1357 Assessment Report as adopted by the PRAC with all information of a confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8416 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2013. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 3 2. Scientific discussion ................................................................................ 3 2.1. Clinical aspects .................................................................................................... 4 2.1.1. Clinical safety .................................................................................................... 4 2.1.2. Clinical efficacy ............................................................................................... 22 2.2. Risk minimisation activities .................................................................................. 29 2.3. Product information ............................................................................................ 31 2.4. Benefit-risk assessment ...................................................................................... 32 2.5. Overall conclusion .............................................................................................. 32 3. Communication plan .............................................................................. 33 4. Conclusion and grounds for the recommendation .................................. 33 2 1. Background information on the procedure Cyproterone acetate / ethinylestradiol (CPA/EE) (2mg/0.035mg) is a medicinal product for treatment of androgen-dependent symptoms in women. Marketing authorisation for the innovator product was first granted in Germany in October 1985. Currently, cyproterone acetate/ethinylestradiol (2mg/0.035mg) containing medicinal products have a marketing authorisation in 135 countries and are marketed in 116 countries. In January 2013 the French medicines agency (ANSM) took the decision to suspend cyproterone acetate/ethinylestradiol (2mg/0.035mg) containing medicinal products in France within three months. ANSM considered the risk of venous and arterial thromboembolism (VTE and ATE) to outweigh the benefits in treating acne. In view of the above, on 4 February 2013 France requested the PRAC under Article 107i of Directive 2001/83/EC1 to assess the above concerns regarding thromboembolism and its impact on the benefit- risk balance for cyproterone acetate/ethinylestradiol (2 mg/0.035 mg) containing medicinal products, and to give its opinion on measures necessary to ensure the safe and effective use, and on whether the marketing authorisation for this product should be maintained, varied, suspended or withdrawn. 2. Scientific discussion Cyproterone acetate exerts its anti-androgenic effect by blocking androgen receptors. It also reduces androgen synthesis by a negative feedback effect on the hypothalamo-pituitary-ovarian axis. The exact indication of cyproterone acetate/ethinylestradiol (2mg/0.035mg) containing medicinal products varies between the EU member states. In general, cyproterone acetate/ethinylestradiol (2mg/0.035mg) is considered a treatment of androgenic symptoms in women, such as pronounced forms of acne, seborrhoea, and mild forms of hirsuitism. It may also have limited effects on alopecia androgenetica. Because of its hormonal composition (additional ethinylestradiol component), CPA/EE (2mg/0.035mg) containing medicinal products act simultaneously as contraceptives. Like other ethinylestradiol containing medicinal products, cyproterone acetate/ethinylestradiol (2mg/0.035mg) containing medicinal products are known to increase risk of thromboembolic events (TE). In July 2002, the Pharmacovigilance Working Party (PhVWP) discussed the increased VTE/ATE risk and concluded that the use of CPA/EE (2mg/0.035mg) should be updated regarding the thromboembolic events. The PhVWP wording is entirely incorporated only in 11 member states. Thromboembolic events Thromboembolic events are rare adverse events which usually occur in a vein of the leg (deep vein thrombosis). When diagnosis is not made and no treatment is started, or when the vein thrombosis does not give any clear symptoms, the clot can move upwards to the lung (pulmonary embolism). Misdiagnosis is a realistic possibility since TE has diffuse symptoms and is a rare event in population of healthy young women. Overall, VTE could be fatal in 1-2% of the cases2. Known risk factors for VTE include history of VTE, pregnancy, trauma, surgery, immobilization (e.g. after surgery or long flights), obesity, and smoking (i.e. all situations of a prothrombotic state). Also 1 French assessment report February 2013 Rationale for the triggering of procedure under Article 107i of Directive 2001/83/EC on cyproterone/ethinylestradiol (2mg/0.035mg) presented by ANSM, France 2 CHMP public assessment report combined oral contraceptives and venous thromboembolism. EMEA/CPMP/2201/01/en/final (2001) 3 there are certain hereditary thrombophilic defects that increase the risk. 3, 4 Checking personal and family history of VTE before prescribing EE-containing medicinal products (e.g. combined oral contraceptives (COC)) is, therefore, recommended. It has been shown that risk of VTE is highest during the first year a woman starts COCs 2,5 or when she restarts after a period of non-use of at least 1 month.6 After an initially higher risk (the first year), the risk drops to a constant lower level. Current alternative treatments Topical therapies are applied for mild to moderate acne without hyperandrogenic state. They include benzoylperoxide, retinoids, antibiotics, salicylic acid, and azelaic acid. Treatment with combined hormonal contraceptives is also proposed. Alternative treatments for (serious) acne are long-term antibiotics (topical or systemic, with risk of resistance and in some cases teratogenicity), keratolytics, and retinoids (topical or systemic, with risk of teratogenicity). The systemic form of isotretinoin may only be prescribed by dermatologists as a second line of treatment. It is hepatotoxic and teratogenic, therefore is subject to a pregnancy prevention plan and regular liver function testing. For the specific combination of symptoms of acne and especially hirsutism in the context of androgen sensitivity, only one licensed alternative therapy is available, i.e. monotherapy with cyproterone acetate (Androcur 10, 50, and 100 mg). However, CPA monotherapy (exposing the patient to a higher dose of CPA) should be combined with adequate hormonal contraception because of foetotoxic effects and could therefore not be used as monotherapy. In addition, there are experimental pharmacological treatments for severe androgenic symptoms (especially hirsutism), such as spironolactone, gonadotropin-releasing hormone- (GnRH-) agonists, ketoconazole, metformin, and pioglitazone. 2.1. Clinical aspects 2.1.1. Clinical safety The PRAC reviewed all available data from clinical studies, pharmacoepidemiological studies, published literature, post-marketing experience on the safety of cyproterone acetate/ ethinylestradiol (2mg/0.035mg) containing medicinal products, as well as stakeholders’ submissions in particular with regards to the thromboembolic events. Thromboembolic events Clinical studies To assess venous and thromboembolic effects from clinical studies with cyproterone acetate/ethinylestradiol (2mg/0.035mg) containing medicinal products only clinical studies that documented relevant adverse events were considered. 3 van Vlijmen EFW et al., (2007). Oral contraceptives and the absolute risk of venous thromboembolism in women with single or multiple thrombophilic defects. Arch Int Med ;167:282-89. 4 van Vlijmen EFW et al., (2011). Thrombotic risk during oral contraceptive use and pregnancy in women with factor V Leiden or prothrombin mutation: a rational approach to contraception. Blood ;118:20551-61. 5 Jick et al. (1995) Risk of idiopathic cardiovascular death and non-fatal venous thromboembolism in women using roal contraceptives with differing progestagen components. Lancet;346:1589-93 6 Additional calculations based on Dinger et al., (2007). The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation. Contraception, 75 (5):344-35 4 The following table presents the MAH (originator)-sponsored phase-III clinical trials providing information on safety of the products. The total number of patients exposed in these studies amounts to 2455. Table 1 Company-sponsored phase III clinical trials Report Main objective Duration of Treatment groups, CPA/EE Women events no./Protocol no. (short title) treatment No. of women (Full Years(WY)** Analysis Set) 6669 / 82009 Symptoms of 6-9 cycles Diane-35: 218 164 (D35) 0 (Basis of androgenization Diane-50: 207 155 (D50) submission application) 8186 / 83194 Symptoms of Up to 36 Diane-35: 1161 3483 0 androgenization Cycle cycles Aydinlik et al., control Contraceptive 1990 Efficacy 13546 / JPH01293 Antiandrogenic effects 6 cycles Diane-35: 20 10